Use of norepinephrine reuptake inhibitors for the treatment of cognitive failure

ABSTRACT

Selective norepinephrine reuptake inhibitors, particularly atomoxetine, reboxetine and 2-alkylthio substituted phenoxyphenyl propylamines, are used for the treatment of cognitive failure, including cognitive failure due to dementia, delirium and schizophrenia.

The invention belongs to the fields of pharmaceutical chemistry andcentral nervous system medicine, and provides a method of treatment forcognitive failure.

Cognitive failure is the dysfunction or loss of cognitive functions, theprocesses by which knowledge is acquired, retained, and used. Anestimated 2% of all Americans have some form and degree of cognitivefailure, with about 15% of those over the age of 65 affected. Cognitivefailure is most commonly due to delirium or dementia, but it may alsooccur in association with a number of other disorders.

A delerium is characterized by a disturbance of consciousness and achange in cognition that develop over a short period of time. Dementiais a chronic deterioration of intellectual function and other cognitiveskills severe enough to interfere with the ability to perform activitiesof daily living. Although dementia may occur at any age, it primarilyaffects the elderly, presenting in more than 15% of persons over 65years of age and in as many as 40% of persons over 80 years old.Dementia accounts for more than half of nursing home admissions.Dementia due to Alzheimer's disease affects four million Americans, atan annual cost of about $90 billion, including medical and nursing homecare, social services, lost productivity, and early death. Alzheimer'sdisease accounts for more than 65% of the dementias in the elderly.

Non-Alzheimer's dementias include Lewy body dementia, vascular dementia,and Binswanger's dementia (subcortical arteriosclerotic encephalopathy).Dementia may also appear in patients with Parkinson's disease,progressive supranuclear palsy, Huntington's disease (chorea), Pick'sdisease, frontal lobe dementia syndromes, dementia pugilistica,normal-pressure hydrocephalus, subdural hematoma, Creutzfeldt-Jakobdisease, Gerstmann-Straussler-Scheinker disease, general paresis, AIDS,and schizophrenia.

Current treatments for cognitive failure include compounds that enhancecholinergic transmission such as donepezil, rivastigmine, and tacrine.The use of these agents is limited by side effects including changes invision or balance, diarrhea, dizziness, fainting spells or falls,increase in frequency of passing urine or incontinence, nervousness,agitation, increased confusion, skin rash or hives, slow heartbeat orpalpitations, stomach pain, sweating, uncontrollable movements, unusualbleeding or bruising, red or purple spots on the skin, vomiting, andweight loss. Another therapy is the administration of the ergothydergine. Hydergine therapy may require six months to determine whetherthe drug has been effective, and side effects include nausea.

Additional therapies are needed for the treatment of cognitive failurethat are more efficacious and better tolerated than treatments that arecurrently available.

The present invention provides a method for the treatment of cognitivefailure that comprises administering to a mammal in need of suchtreatment an effective amount of a selective norepinephrine reuptakeinhibitor.

The present invention provides a method for the treatment of cognitivefailure that relies on a novel mechanism of action. This methodcomprises treating a mammal suffering from cognitive failure with acompound that is a selective norepinephrine reuptake inhibitor. Thismechanism is operative in mammals and the preferred mammal is a human.

The present invention also provides the use of a selectivenorepinephrine reuptake inhibitor for the preparation of a medicamentuseful for the treatment or prevention of cognitive failure.

The present invention provides a method for the treatment of cognitivefailure. The term “cognitive failure”, as used herein, refers to thespectrum of cognitive dysfunctions ranging from mild cognitiveimpairment to deterioration of intellectual function and other cognitiveskills severe enough to interfere with the ability to perform activitiesof daily living.

Many compounds, including those discussed at length below, are selectivenorepinephrine reuptake inhibitors, and no doubt, many more will beidentified in the future. In the practice of the present invention, itis intended to include reuptake inhibitors which show 50% effectiveconcentrations of about 1000 nM or less, in the protocol described byWong et al., Drug Development Research, 6, 397 (1985). Thenorepinephrine reuptake inhibitors useful for the method of the presentinvention are characterized in being selective for the inhibition ofneurotransmitter reuptake relative to their ability to act as directagonists or antagonists at other receptors. It is preferred that thecompounds useful for the method of the present invention are selectivefor the inhibition of norepinephrine reuptake relative to direct agonistor antagonist activity at other receptors by a factor of at least ten.Preferably, compounds useful for the method of the present invention areselective for the inhibition of norepinephrine reuptake relative todirect agonist or antagonist activity at other receptors by a factor ofat least one hundred. Norepinephrine reuptake inhibitors useful for themethod of the present invention include, but are not limited to:

Atomoxetine (formerly known as tomoxetine),(R)-(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, is usuallyadministered as the hydrochloride salt. Atomoxetine was first disclosedin U.S. Pat. No. 4,314,081. The word “atomoxetine” will be used here torefer to any acid addition salt or the free base of the molecule. See,for example, Gehlert, et al., Neuroscience Letters, 157, 203-206 (1993),for a discussion of atomoxetine's activity as a norepinephrine reuptakeinhibitor;

The compounds of formula I:

wherein X is C₁-C₄ alkylthio, and Y is C₁-C₂ alkyl or a pharmaceuticallyacceptable salt thereof. The compounds of formula I were described inU.S. Pat. No. 5,281,624, of Gehlert, Robertson, and Wong, and inGehlert, et al., Life Sciences, 55(22), 1915-1920, (1995). The compoundsare there taught to be inhibitors of norepinephrine reuptake in thebrain. It is also explained that the compounds exist as stereoisomers,and that they accordingly include not only the racemates, but also theisolated individual isomers as well as mixtures of the individualisomers. For example, the compounds of formula I include the followingexemplary species:

-   N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propylamine benzoate;-   (R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)propylamine    hydrochloride;-   (S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propylamine;-   N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propylamine malonate;-   (S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)propylamine    naphthalene-2-sulfonate;-   (R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine; and

Reboxetine (Edronax™), 2-[α-(2-ethoxy)phenoxybenzyl]morpholine, isusually administered as the racemate. It was first taught by U.S. Pat.No. 4,229,449, which describes its utility for the treatment ofdepression. Reboxetine is a selective norepinephrine reuptake inhibitor.The term “reboxetine” will be used here to refer to any acid additionsalt or the free base of the molecule existing as the racemate or eitherenantiomer.

While all compounds exhibiting norepinephrine reuptake inhibition areuseful for the methods of the present invention, certain are preferred.It is preferred that the norepinephrine reuptake inhibitor is selectivefor the reuptake of norepinephrine over the reuptake of otherneurotransmitters. It is also preferred that the norepinephrine reuptakeinhibitor does not exhibit significant direct agonist or antagonistactivity at other receptors. It is especially preferred that thenorepinephrine reuptake inhibitor be selected from atomoxetine,reboxetine, or (R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine.The use of atomoxetine hydrochloride for the methods of the presentinvention is the most preferred embodiment of the present invention.

A further embodiment of this invention comprises the administration of acomposition that exhibits selective norepinephrine reuptake inhibitoractivity. The composition may be composed of one or more agents that,individually or together, are selective inhibitors of norepinephrinereuptake.

The dosages of the drugs used in the present invention must, in thefinal analysis, be set by the physician in charge of the case usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patientincluding diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferreddosages, can and will be provided here.

Atomoxetine: In adults and older adolescents: from about 5 mg/day toabout 200 mg/day; preferably in the range from about 60 to about 150mg/day; more preferably from about 60 to about 130 mg/day; and stillmore preferably from about 50 to about 120 mg/day; in children andyounger adolescents: from about 0.2 to about 3.0 mg/kg/day; preferablyin the range from about 0.5 to about 1.8 mg/kg/day;

Compounds of formula I: from about 0.01 mg/kg to about 20 mg/kg;preferred daily doses will be from about 0.05 mg/kg to 10 mg/kg; ideallyfrom about 0.1 mg/kg to about 5 mg/kg;

Reboxetine: from about 1 to about 30 mg, once to four times/day;preferred, from about 5 to about 30 mg once/day.

Cognitive failure presents in patients suffering from a number of otherdisorders. The present invention includes the use of a norepinephrinereuptake inhibitor to treat cognitive failure presenting alone or wherecognitive failure is associated with another disorder. Schizophrenicpatients, for example, commonly exhibit symptoms that include cognitivefailure. An embodiment of the present invention, therefore, is the useof a norepinephrine reuptake inhibitor to treat cognitive failureassociated with schizophrenia. Patients suffering from schizophreniaalso frequently exhibit negative symptoms such as flat affect,asociality, anergia, avolition, and anhedonia. A further embodiment ofthe present invention is the use of a norepinephrine reuptake inhibitorto treat the negative symptoms of schizophrenia.

The invention further provides a method for treating a patient sufferingfrom or susceptible to psychosis, comprising administering to saidpatient an effective amount of a first component which is anantipsychotic, in combination with an effective amount of a secondcomponent which is a norepinephrine reuptake inhibitor. The inventionalso provides a pharmaceutical composition that comprises a firstcomponent that is an antipsychotic, and a second component that is anorepinephrine reuptake inhibitor.

In the general expressions of this aspect of the present invention, thefirst component is a compound that acts as an antipsychotic. Theantipsychotic may be either a typical antipsychotic, such ashaloperidol, or an atypical antipsychotic. The essential feature of anatypical antipsychotic is less acute extrapyramidal symptoms, especiallydystonias, associated with therapy as compared to a typicalantipsychotic such as haloperidol. Clozapine, the prototypical atypicalantipsychotic, differs from the typical antipsychotics with thefollowing characteristics: (1) greater efficacy in the treatment ofoverall psychopathology in patients with schizophrenia nonresponsive totypical antipsychotics; (2) greater efficacy in the treatment ofnegative symptoms of schizophrenia; and (3) less frequent andquantitatively smaller increases in serum prolactin concentrationsassociated with therapy (Beasley, et al., Neuropsychopharma-cology,14(2), 111-123, (1996)). Although both typical and atypicalantipsychotics are useful for these methods and formulations of thepresent invention, it is preferred that the first component compound isan atypical antipsychotic.

Typical antipsychotics include, but are not limited to:

Chlorpromazine, 2-chloro-10-(3-dimethylaminopropyl)phenothiazine, isdescribed in U.S. Pat. No. 2,645,640. Its pharmacology has been reviewed(Crismon, Psychopharmacol. Bul., 4, 151 (October 1967);

Droperidol,1-(1-[3-(p-fluorobenzoyl)propyl]-1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone,is described in U.S. Pat. No. 3,141,823;

Haloperidol,4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone,is described in U.S. Pat. No. 3,438,991. Its therapeutic efficacy inpsychosis has been reported (Beresford and Ward, Drugs, 33, 31-49(1987);

Thioridazine,1-hydroxy-10-[2-(1-methyl-2-pyridinyl)ethyl]-2-(methylthio)phenothiazinehydrochloride, was described by Bourquin, et al. (Helv. Chim. Acta, 41,1072 (1958)). Its use as an antipsychotic has been reported (Axelsson,et al., Curr. Ther. Res., 21, 587 (1977)); and

Trifluoperazine,10-[3-(4-methyl-1-piperazinyl)propyl]-2-trifluoromethylphenthiazinehydrochloride, is described in U.S. Pat. No. 2,921,069.

Atypical antipsychotics include, but are not limited to: Olanzapine,2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,is a known compound and is described in U.S. Pat. No. 5,229,382 as beinguseful for the treatment of schizophrenia, schizophreniform disorder,acute mania, mild anxiety states, and psychosis;

Clozapine,8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine, isdescribed in U.S. Pat. No. 3,539,573. Clinical efficacy in the treatmentof schizophrenia is described (Hanes, et al., Psychopharmacol. Bull.,24, 62 (1988));

Risperidone,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one,and its use in the treatment of psychotic diseases are described in U.S.Pat. No. 4,804,663;

Sertindole,1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]imidazolidin-2-one,is described in U.S. Pat. No. 4,710,500. Its use in the treatment ofschizophrenia is described in U.S. Pat. Nos. 5,112,838 and 5,238,945;

Quetiapine,5-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol,and its activity in assays which demonstrate utility in the treatment ofschizophrenia are described in U.S. Pat. No. 4,879,288. Quetiapine istypically administered as its (E)-2-butenedioate (2:1) salt; and

Ziprasidone,5-[2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,is typically administered as the hydrochloride monohydrate.

The compound is described in U.S. Pat. Nos. 4,831,031 and 5,312,925. Itsactivity in assays which demonstrate utility in the treatment ofschizophrenia are described in U.S. Pat. No. 4,831,031.

Similarly, when this aspect of the invention is regarded in its broadestsense, the second component compound is a compound that functions as anorepinephrine reuptake inhibitor as described above.

It will be understood that while the use of a single antipsychotic as afirst component compound is preferred, combinations of two or moreantipsychotics may be used as a first component if necessary or desired.Similarly, while the use of a single norepinephrine reuptake inhibitoras a second component compound is preferred, combinations of two or morenorepinephrine reuptake inhibitors may be used as a second component ifnecessary or desired.

While all combinations of first and second component compounds areuseful and valuable, certain combinations are particularly valued andare preferred, as follows:

-   -   olanzapine/atomoxetine    -   olanzapine/reboxetine    -   olanzapine/(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine    -   clozapine/atomoxetine    -   risperidone/atomoxetine    -   sertindole/atomoxetine    -   quetiapine/atomoxetine    -   ziprasidone/atomoxetine

In general, combinations and methods of treatment using olanzapine asthe first component are preferred. Furthermore, combinations and methodsof treatment using atomoxetine as the second component are preferred.Especially preferred are combinations and methods of treatment usingolanzapine as the first component and atomoxetine as the secondcomponent. It is especially preferred that when the first component isolanzapine, it will be the Form II olanzapine as described in U.S. Pat.No. 5,736,541.

It is further preferred that the Form II olanzapine polymorph will beadministered as the substantially pure Form II olanzapine polymorph. Asused herein “substantially pure” refers to Form II associated with lessthan about 5% Form I, preferably less than about 2% Form I, and morepreferably less than about 1% Form I. Further, “substantially pure” FormII will contain less than about 0.5% related substances, wherein“related substances” refers to undesired chemical impurities or residualsolvent or water. In particular, “substantially pure” Form II shouldcontain less than about 0.05% content of acetonitrile, more preferably,less than about 0.005% content of acetonitrile. Additionally, thepolymorph of the invention should contain less than 0.5% of associatedwater.

Although Form II olanzapine is preferred it will be understood that asused herein, the term “olanzapine” embraces all solvate and polymorphicforms unless specifically indicated.

It will be understood by the skilled reader that most or all of thecompounds used in the present invention are capable of forming salts,and that the salt forms of pharmaceuticals are commonly used, oftenbecause they are more readily crystallized and purified than are thefree bases. In all cases, the use of the pharmaceuticals described aboveas salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them. Especially preferredpharmaceutically acceptable salts are those formed with hydrochloricacid.

The dosages of the first component drugs used in this aspect of thepresent invention must, in the final analysis, be set by the physicianin charge of the case, using knowledge of the drugs, the properties ofthe drugs in combination as determined in clinical trials, and thecharacteristics of the patient, including diseases other than that forwhich the physician is treating the patient. General outlines of thedosages, and some preferred dosages, can and will be provided here.Dosage guidelines for some of the drugs will first be given separately;in order to create a guideline for any desired combination, one wouldchoose the guidelines for each of the component drugs.

-   -   Chlorpromazine: from about 25-75 mg daily to about 75-150 mg        daily;    -   Droperidol: about 5 mg by injection;    -   Haloperidol: from about 1-15 mg/day to about 100 mg/day        administered orally or by injection;    -   Thioridazine: about 75-150 mg daily;    -   Trifluoperazine: from about 4-10 mg/day to about 15-20 mg/day;    -   Olanzapine: from about 0.25 to 50 mg, once/day; preferred, from        1 to 30 mg, once/day; and most preferably 1 to 25 mg once/day;    -   Clozapine: from about 12.5 to 900 mg daily; preferred, from        about 150 to 450 mg daily;    -   Risperidone: from about 0.25 to 16 mg daily; preferred from        about 2-8 mg daily;    -   Sertindole: from about 0.0001 to 1.0 mg/kg daily;    -   Quetiapine: from about 1.0 to 40 mg/kg given once daily or in        divided doses;    -   Ziprasidone: from about 5 to 500 mg daily; preferred from about        50 to 100 mg daily.

In more general terms, one would create a combination of the presentinvention by choosing a dosage of first and second component compoundsaccording to the spirit of the above guideline.

The adjunctive therapy aspect of the present invention is carried out byadministering a first component together with the second component inany manner that provides effective levels of the compounds in the bodyat the same time. Oral administration of the adjunctive combination ispreferred. Both components may be administered together, in a singledosage form, or may be administered separately. However, oraladministration is not the only route or even the only preferred route.For example, transdermal administration may be very desirable forpatients who are forgetful or petulant about taking oral medicine.Administration by the percutaneous, intravenous, intramuscular,intranasal or intrarectal route may be prudent in particularcircumstances. The route of administration may be varied in any way,limited by the physical properties of the drugs, the convenience of thepatient and the caregiver, and other relevant circumstances (Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).

The adjunctive combination may be administered as a singlepharmaceutical composition, and so pharmaceutical compositionsincorporating both compounds are important embodiments of the presentinvention. Such compositions may take any physical form that ispharmaceutically acceptable, but orally usable pharmaceuticalcompositions are particularly preferred. Such adjunctive pharmaceuticalcompositions contain an effective amount of each of the compounds, whicheffective amount is related to the daily dose of the compounds to beadministered. Each adjunctive dosage unit may contain the daily doses ofall compounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compounds. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compounds. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material that can serve as a vehicle or medium forthe active ingredient. Suitable carriers or excipients are well known inthe art. The pharmaceutical composition may be adapted for oral,inhalation, parenteral, or topical use and may be administered to thepatient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds useful for the method of the present invention may beadministered orally, for example, with an inert diluent or capsules orcompressed into tablets. For the purpose of oral therapeuticadministration, the compounds may be incorporated with excipients andused in the form of tablets, troches, capsules, elixirs, suspensions,syrups, wafers, chewing gums and the like. These preparations shouldcontain at least 4% of the compound of the present invention, the activeingredient, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of the compound present in compositions is such that a suitabledosage will be obtained. Preferred compositions and preparations usefulfor the methods of the present invention may be determined by a personskilled in the art.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials that modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other coatingagents. A syrup may contain, in addition to the present compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

A formulation useful for the administration of R(−)-N-methyl3-((2-methylphenyl)oxy)-3-phenyl-1-aminopropane hydrochloride(atomoxetine) comprises a dry mixture of R-(−)-N-methyl3-((2-methylphenyl)oxy)-3-phenyl-1-aminopropane hydrochloride with adiluent and lubricant. A starch, such as pregelatinized corn starch, isa suitable diluent and a silicone oil, such as dimethicone, a suitablelubricant for use in hard gelatin capsules. Suitable formulations areprepared containing about 0.4 to 26% R-(−)-N-methyl3-((2-methylphen-yl)oxy)-3-phenyl-1-aminopropane hydrochloride, about 73to 99% starch, and about 0.2 to 1.0% silicone oil. The following tablesillustrate particularly preferred atomoxetine formulations: 2.5 mg 5 mg10 mg 18 mg 20 mg 25 mg 40 mg 60 mg Ingredient (%) R-(−)-N-methyl 3-1.24 2.48 4.97 8.94 9.93 12.42 19.87 22.12 ((2-methylphenyl) oxy)-3-phenyl-1- aminopropane hydrochloride Dimethicone 0.5 0.5 0.5 0.5 0.5 0.50.5 0.5 Pregelatinized 98.26 97.02 94.53 90.56 89.57 87.08 79.63 77.38Starch Ingredient (mg/capsule) R-(−)-N-methyl 3- 2.86 5.71 11.43 20.5722.85 28.57 45.71 68.56 ((2-methylphenyl) oxy)-3- phenyl-1- aminopropanehydrochloride Dimethicone 1.15 1.15 1.15 1.15 1.15 1.15 1.15 1.55Pregelatinized 225.99 223.14 217.42 208.28 206.00 200.28 183.14 239.89Starch Capsule Fill Weight 230 230 230 230 230 230 230 310 (mg) CapsuleSize 3 3 3 3 3 3 3 2

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations typically contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about90% of the weight thereof. The amount of the compound of formula Ipresent in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions may also include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations may be determined by one skilled in the art.

Inhibition or Norepinephrine Reuptake

The ability of compounds to inhibit the reuptake of norepinephrine maybe measured by the general procedure of Wong, et al., supra.

Male Sprague-Dawley rats weighing 150-250 gm are decapitated and brainsare immediately removed. Cerebral cortices are homogenized in 9 volumesof a medium containing 0.32 M sucrose and 10 mM glucose. Crudesynaptosomal preparations are isolated after differential centrifugationat 1000×g for 10 minutes and 17,000×g for 28 minutes. The final pelletsare suspended in the same medium and kept in ice until use within thesame day.

Synaptosomal uptake of ³H-norepinephrine is determined as follows.Cortical synaptosomes (equvalent to 1 mg of protein) are incubated at37° C. for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10mM glucose, 0.1 mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50nM ³H-norepinephrine. The reaction mixture is immediately diluted with 2mL of ice-chilled Krebs-bicarbonate buffer and filtered under vacuumwith a cell harvester (Brandel, Gaithersburg, Md.). Filters are rinsedtwice with approximately 5 mL of ice-chilled 0.9% saline and the uptakeof ³H-norepinephrine assessed by liquid scintillation counting.Accumulation of ³H-norepinephrine at 4° C. is considered to bebackground and is subtracted from all measurements. The concentration ofthe test compound required to inhibit 50% of the ³H-norepinephrineaccumulation (IC₅₀ values) are determined by linear regression analysis.

The present invention provides a method for the treatment of cognitivefailure. Cognitive failure may present in patients suffering from anumber of disorders. The methods of the present invention are useful forthe treatment of cognitive failure associated with disorders classifiedin the Diagnostic and Statistical Manual of Mental Disorders, 4thVersion, published by the American Psychiatric Association (DSM-IV). TheDSM code numbers are supplied below for the convenience of the reader.Delirium Due to a General Medical Condition 293.0 Delirium Not OtherwiseSpecified 780.09 Dementia of the Alzheimer's Type Early Onset withDelirium 290.11 Early Onset with Delusions 290.12 Early OnsetUncomplicated 290.10 Late Onset with Delirium 290.3 Late Onset withDelusions 290.20 Late Onset Uncomplicated 290.0 Vascular Dementia WithDelirium 290.41 With Delusions 290.42 Uncomplicated 290.40 Dementia Dueto HIV Disease 294.1 Dementia Due to Head Trauma 294.1 Dementia Due toParkinson's Disease 294.1 Dementia Due to Huntington's Disease 294.1Dementia Due to Pick's Disease 290.10 Dementia Due to Creutzfeldt-JakobDisease 290.10 Dementia Due to Other General Medical Conditions 294.1Dementia Not Otherwise Specified 294.8 Amnestic Disorder Due to aGeneral Medical 294.0 Condition Amnestic Disorder Not OtherwiseSpecified 294.8 Cognitive Disorder Not Otherwise Specified 294.9Paranoid Type Schizophrenia 295.30 Disorganized Type Schizophrenia295.10 Catatonic Type Schizophrenia 295.20 Undifferentiated TypeSchizophrenia 295.90 Residual Type Schizophrenia 295.60 SchizophreniformDisorder 295.40 Schizoaffective Disorder 295.70The skilled artisan will appreciate that the disorders listed above areillustrative of those indications where cognitive failure may appear,and is not intended to limit the scope of the present invention in anyway.

Psychotic conditions to be treated by the adjunctive therapy aspect ofthe present invention include schizophrenia, schizophreniform diseases,acute mania, and schizoaffective disorders. The titles given theseconditions represent multiple disease states. The following listillustrates a number of these disease states, many of which areclassified in the Diagnostic and Statistical Manual of Mental Disorders,4th Edition, published by the American Psychiatric Association (DSM).The DSM code numbers for these disease states are supplied below, whenavailable, for the convenience of the reader. Paranoid TypeSchizophrenia 295.30 Disorganized Type Schizophrenia 295.10 CatatonicType Schizophrenia 295.20 Undifferentiated Type Schizophrenia 295.90Residual Type Schizophrenia 295.60 Schizophreniform Disorder 295.40Schizoaffective Disorder 295.70

The present invention is also useful for the treatment of cognitivefailure related to the onset of menopause.

The method of the present invention is effective in the treatment ofpatients who are children, adolescents or adults, and there is nosignificant difference in the symptoms or the details of the manner oftreatment among patients of different ages. In general terms, however,for purposes of the present invention, a child is considered to be apatient below the age of puberty, an adolescent is considered to be apatient from the age of puberty up to about 18 years of age, and anadult is considered to be a patient of 18 years or older.

EXAMPLE 1

The immediate-early gene, c-fos, and its protein products have beenincreasingly utilized as markers for neuronal activation (Dragunow andFaull, J. Neurosci. Methods, 29, 261-265 (1989); Morgan and Curran,Prog. In Brain Res., 86, 287-294 (1990); Robertson, et al., J.Pharmacol. Exp. Ther., 271, 1058-1066 (1994)). C-fos activation ismeasured as illustrated below for atomoxetine.

Two hours after administration of atomoxetine (3 mg/kg, i.p.), the ratswere deeply anesthetized with sodium pentobarbital (60 mg/kg, i.p.) andtranscardially perfused with 100 ml of phosphate buffered saline (PBS)followed by 100 ml of 4% paraformaldehyde in PBS. The brain was rapidlyremoved, postfixed for 90 min in 4% paraformaldehyde and then wastransferred to 30% sucrose at 40 C until saturated. After quickfreezing, serial 30 μm sections were cut and placed in PBS untilprocessed for immunohistochemistry. In brief, sections were incubated inPBS containing blocking serum and 0.5% Triton-X 100 for 1 hour. Sectionswere then incubated with anti-Fos antibody (Santa Cruz Biotechnology,Inc.) at 4° C. overnight. Visualization of the Fos-like immunoreactivitywas performed with a Vectastain ABC Elite Kit (Vector Labs, Burlingame,Calif.) using the standard protocol supplied with the kit.Nickel-intensified diaminobenzidine (DAB) was used as the chromagen toyield a gray-black precipitation product. Following visualization of theFos immunoreactivity, the sections were mounted on gelatin-coated glassslides and allowed to dry. The sections were then dehydrated and coverslipped. Fos expressing cells were quantitated using the MCID M2 imagingsystem (Imaging Research, St. Catherines, Ontario).

Surprisingly, atomoxetine increased the expression of c-fos only in thecortical areas as demonstrated by the data in the following table.Prefrontal Nucleus Treatment Cortex** Accumbens** Striatum** Vehicle 80± 28 129 ± 33 118 ± 26 Atomoxetine 296 ± 26* 152 ± 44 102 ± 35*= p < 0.001**Fos positive cells/mm²

1-15. (canceled).
 16. A method of treating cognitive failure, comprisingadministering to a human patient in need thereof an effective amount ofa selective norepinephrine reuptake inhibitor selected from the groupconsisting of atomoxetine and a compound of formula I:

wherein X is C₁-C₄ alkylthio, and Y is C₁-C₂ alkyl, or apharmaceutically acceptable salt thereof.
 17. The method of claim 16,wherein said selective norepinephrine reuptake inhibitor is atomoxetine.18. The method of claim 17, wherein said atomoxetine is in the form of ahydrochloride salt.
 19. The method of claim 16, wherein said cognitivefailure is associated with a dementia.
 20. The method of claim 19,wherein said dementia is selected from the group consisting of dementiaof the Alzheimer's type, vascular dementia, dementia due to head trauma,dementia due to Parkinson's Disease, dementia due to other generalmedical conditions, and dementia not otherwise specified.
 21. The methodof claim 20, wherein said human patient is an older adolescent or anadult, and said atomoxetine is administered in the form of ahydrochloride salt in a dose of from about 5 mg/day to about 200 mg/day.22. The method of claim 20, wherein said human patient is a child or ayounger adolescent, and said atomoxetine is administered in the form ofa hydrochloride salt in a dose of from about 0.2 mg/kg/day to about 3.0mg/kg/day.
 23. The method of claim 16, wherein said cognitive failure isassociated with a delirium.
 24. The method of claim 23, wherein saiddelirium is selected from the group consisting of a delirium due to ageneral medical condition and a delirium not otherwise specified. 25.The method of claim 24, wherein said human patient is an olderadolescent or an adult, and said atomoxetine is administered in the formof a hydrochloride salt in a dose of from about 5 mg/day to about 200mg/day.
 26. The method of claim 24, wherein said human patient is achild or a younger adolescent, and said atomoxetine is administered inthe form of a hydrochloride salt in a dose of from about 0.2 mg/kg/dayto about 3.0 mg/kg/day.
 27. The method of claim 16, wherein saidcognitive failure is associated with schizophrenia.
 28. The method ofclaim 27, wherein said human patient is an older adolescent or an adult,and said atomoxetine is administered in the form of hydrochloride saltin a dose of from about 5 mg/day to about 200 mg/day.
 29. The method ofclaim 27, wherein said human patient is a child or a younger adolescent,and said atomoxetine is administered in the form of a hydrochloride saltin a dose of from about 0.2 mg/kg/day to about 3.0 mg/kg/day.
 30. Amethod of treating negative symptoms of schizophrenia, comprisingadministering to a human patient in need thereof an effective amount ofa selective norepinephrine reuptake inhibitor selected from the groupconsisting of atomoxetine, reboxetine, and a compound of formula I:

wherein X is C₁-C₄ alkylthio, and Y is C₁-C₂ alkyl, or apharmaceutically acceptable salt thereof.
 31. The method of claim 30,wherein said human patient is an older adolescent or an adult, and saidatomoxetine is administered in the form of hydrochloride salt in a doseof from about 5 mg/day to about 200 mg/day.
 32. The method of claim 30,wherein said human patient is a child or a younger adolescent, and saidatomoxetine is administered in the form of a hydrochloride salt in adose of from about 0.2 mg/kg/day to about 3.0 mg/kg/day.
 33. A method oftreating psychosis, comprising administering to a human patient in needthereof an effective amount of a selective norepinephrine reuptakeinhibitor selected from the group consisting of atomoxetine, reboxetine,and a compound of formula I:

wherein X is C₁-C₄ alkylthio, and Y is C₁-C₂ alkyl, or apharmaceutically acceptable salt thereof, in combination with aneffective amount of an antipsychotic.
 34. The method of claim 33,wherein said psychosis is selected from the group consisting ofschizophrenia, a schizophreniform disease, acute mania, and aschizoaffective disorder.
 35. The method of claim 34, wherein said humanpatient is an older adolescent or an adult, and said atomoxetine isadministered in the form of hydrochloride salt in a dose of from about 5mg/day to about 200 mg/day.
 36. The method of claim 34, wherein saidhuman patient is a child or a younger adolescent, and said atomoxetineis administered in the form of a hydrochloride salt in a dose of fromabout 0.2 mg/kg/day to about 3.0 mg/kg/day.